GENOTYPE-PHENOTYPE CORRELATION STUDY OF CTNNB1 SYNDROME AND INVESTIGATION OF NOVEL APPROACHES TO ITS TREATMENT

CTNNB1 syndrome is a rare neurodevelopmental disorder, which is caused by de novo occurrence of loss-of-function mutations within one allele of the CTNNB1 gene. It manifests itself in an array of motor, cognitive and behavioral impairments that are directly linked to the insufficient production of β-catenin protein, encoded by CTNNB1. The definite diagnosis of CTNNB1 syndrome symptoms can only be established by genetic testing. The CTNNB1 syndrome is a progressive, debilitating and under recognized disease resembling cerebral palsy, but relevant clinical data on the syndrome is sparse. The primary aim of the proposed project is to conduct a genotype-phenotype correlation study in order to evaluate the relationship between type and location of genetic mutations and disease phenotype severity. Furthermore, we plan to support the correlation study with biochemical characterization of the mutations. Finally, as there is currently no treatment available for this syndrome, we want to exploit the potential of novel DNA and RNA modification strategies such as prime editing for the genomic correction of the mutation, spliceosome-mediated RNA trans-splicing for replacement of exons bearing mutations at the transcriptional level and the use of antisense oligonucleotides (ASO) for enhancement of wild type allele β-catenin expression levels through the repression of endogenous β-catenin inhibitory processes. This project proposal represents a comprehensive interdisciplinary approach to the study of CTNNB1 syndrome which can serve as a reference for both clinicians and developers of gene therapies and could serve as a foundation for treatment strategies for rare genetic diseases. Considering our promising preliminary results, expertise of the PI and other members of the consortium, established international collaborations the project is likely to advance understanding and therapeutic options of this disease.